Set Up A Clinical Trial Biology Essay

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According to the NHS clinical trials is a particular type of research that tests one treatment against another. It may involve either patients or people in good health, or both. According to one in seven people in the UK suffer from migraine with an average of thirteen attacks each year. Migraine affects 11% of adult population in western countries and its prevalence is lowest in Asia and Africa.It has a high prevalence in people aged 25-55 and it is twice as common in females as in male. Stewart et al (1989) studies of migraine found an incidence of 601 per100, 000 in females and 222 per 100,000 in males in the USA. Migraine costs the UK around Seventeen million per annum and affects all ages and social classes. Due to its high prevalence and the temporary disability it causes Therefore Professor Smith has to test his new drug against other standard treatments for migraine during clinical trials to test its efficacy, safety and to make sure it is more effective or has fewer side effects than other standard treatments before it is released into the market.

When a new potential drug has been identified (such as the drug produced by Professor Smith), several professionals would need to be involved in its development to get it into the market. The company who have created a new potential drug are mainly involved in its development, whether this is through their own research or via organisations they contract research out to. A medical team would need to be assembled to ensure volunteers are safe throughout clinical trials. Other professionals would also be required such as pharmacists and statisticians.

To set up a clinical trial on volunteers and patients Professor Smith has to consider the preclinical development which involves a wide range of non-human studies to check the drug does not produce any hazardous acute effects like bronchoconstriction. Preclinical development is done to make sure the new drug satisfies all requirements that have to be met before it can be first tested on humans. Preclinical studies are tested on laboratory animals; methods of this include pharmacokinetic studies, used to find out the absorption, distribution, metabolism, and elimination of the new compounds. Pharmacodynamic studies are done to explore the effects of the drug on the body at different concentrations and toxicology testing to eliminate genotoxicity and know the maximum non toxic dose of the drug [3] . Preclinical development has to be in compliance with Good Laboratory Practice code to eliminate human error as much as possible and ensure the reliability of the data sent to regulatory authority.

`It is possible to waste too much time in animal studies before testing a drug in man' [4] When preclinical studies in animals are completed, have proved efficacy and toxicology testing has provided a measure of the possible risks, the new compound can now be tested in humans. [5] The two groups of people Professor Smith will use for drug testing in clinical trials are healthy volunteers and volunteer patients. Clinical trials in healthy volunteers would help to determine the tolerability, safety and pharmacokinetics of the new compound while only the dynamic and therapeutic effect can be investigated in volunteer patients. [6] Healthy volunteers are usually paid for partaking in clinical trials, as they don't get any benefit from the treatment received so they are compensated for the discomfort and inconvenience. In comparison, volunteer patients are not paid for taking part in clinical trials, although out of pocket expenses are usually met. [7] 

Clinical trials are performed in four phases and they can be abandoned at any stage if there are found to be safety issues, problems with efficacy or other concerns such as commercial pressures. [8] Phase 1 of clinical trials is usually done with 20-80 healthy volunteers to check that the drug is safe to give to humans, without producing any hazardous side-effects. It is also important for ensuring that the drug is not too toxic, and that the pharmacokinetics and pharmacodynamics of the drug have not deviated from the results obtained from preclinical trials in animals. It is also done to know the effect of different doses of the drug in volunteer patients and how tolerable the drug is. Phases 2 of clinical trials are limited scale clinical trials performed on volunteer patients (100-300) to find out if the drug produces the desired effect and to know the therapeutic dose of the drug under controlled clinical conditions. Uncontrolled dose-ranging studies are also performed during this phase to determine the dose to be used in phase 3. It might also be compared against a placebo. The patients are closely monitored and the efficacy and safety of the drug is further evaluated. Drugs that don't

Phase 3 involves a large scale clinical trial performed on thousands of patients usually between 1000-3000 in different centres to see the effect of the drug in the different places. The effectiveness of the drug is also compared with standard alternatives. Double blind randomised controlled trials are usually performed at this stage to confirm the therapeutic dose, efficacy and safety on a large scale. Phase 3 clinical trials are very expensive and time consuming to organise and run and often take years to complete. The economic benefits of the drug are also assessed during this phase. [9] If the drug is found to be safe at the end of phase 3 it is usually submitted to the regulatory authority along with the preclinical data for product licensing which may take years for approval. During phase 4 of clinical trials the drug is released unto the market after thousands of patients have used the drug for a short period. It is being monitored (post marketing surveillance) to access efficacy and toxicity over a large scale. If there are any adverse effects associated with the new drug it could be still be withdrawn at this stage or just limited to a particular group of patients. [10] 

There are different designs of trials that Professor Smith can use to test the drug, this are controlled, randomisation or blinding techniques. Configurations for clinical trials he could also use include parallel group design and crossover design. When designing a clinical trial for migraine it is important to consider the characteristics of the patient, their age, and the different types of migraine in each patient, how many patients and healthy volunteers to use, choice of dose range, what kind of design to use and how to monitor . Studies should also be done over a wide range of individuals from children to adults (18-65) to the elderly to see if the drug responds differently as glomerular filtration rate reduces with time and with patients with impaired liver or kidney. Clinical trial designs should also be done on healthy individuals first to see the food and other drug interactions before given to patients this is important especially in the elderly patients that use a combination of drugs.

Blinding in clinical trials can either be single blind where the subject does not know if they are prescribed a placebo or new drug at the time of administration. And double-blind where the subjects or doctors, investigators or assessors are ignorant to what treatment is being used. This is done to prevent bias from doctors and subjects from affecting the results and to be able to distinguish the pharmacodynamics effects of the drug from the psychological effects of the act of medication [11] . Double blinding and randomisation are techniques used together to avoid bias and in selection and allocation of subjects. Blinding in clinical trials is usually difficult to achieve and maintain because the pharmacological effects of the active drug can reveal which patients are taking it, or the size, shape, texture, weight and shape of the tablet looking different. It is therefore important to be able to create a placebo drug or have a standard treatment manipulated to have the same packaging and look like the new drug, without compromising the bioequivalence and stability of the manipulated standard treatment.

During clinical trials the new compound is being compared against a placebo or another standard treatment, and this is usually done during phase 3 of clinical trials. To test the new drug for migraine a double blind cross-over trial is the most appropriate clinical trial design. Double blinding should not be used in new compounds from animal laboratory in preclinical studies, until the dose and effects in humans are known. The new drug must have undergone a therapeutic trial and dose-response trial in a classic randomised controlled trial in phase 2. This trial is large scale and is performed as a multicentre trial on hundreds of patients. In a Crossover design, patient receives each of the two treatments in a random order.

During the double blind crossover clinical trial Professor Smith can use 500patients men and women aged 18-65 with different types of migraine such as hemiplegic migraine, ophthalmoplegic migraine, and basilar-type migraine ranging from mild to moderate and severe (chronic) with a frequency of occurrence between 2-4weeks . It should be done in different centres in 10 different countries to see if the effect varies with environment and different genes, with about 50 patients in each country over a period of 40 weeks.

During the trial Professor Smith will compare his new drug against a standard treatment such as aspirin. He along with the patients and other officials (assessors) involved in the trial would be kept in the dark as to which drug each patient takes, this can be done by using different codes.

In each centre with 50 patients the patients can be grouped into three based on the different types of migraine, group A, 16 patients with ages ranging from 18-65 with hemiplegic migraine, group B, 17 patients aged 18-65 with ophthalmoplegic migraine and group C, 17 patients with also aged 18-65 with basilar type migraine. In each group the new drug (N) and aspirin (A) can be given to each patient in a random controlled order, so that 7(A1, B1, C2) patients end up with aspirin and 8(A2, B2, C1) patients the new drug. Therefore 7 patients in A and B and 8 patients in C are administered aspirin. While 8 patients in group A and B and 7 patients C administered the new drug. During the first 15weeks the two different drugs can be administered every 20days and patients monitored with each drug given five times through-out the first phase. After the first 15weeks Professor Smith should have a 5week wash-out period where no treatment will be administered. During the second phase the patients which had the new drug in each group should be given aspirin and the group which had the aspirin should be given

The advantage of crossover designs over parallel design is that each patient can act as their own control so this eliminates subject to subject variation and reduces the number of subjects used. [12] The disadvantage of cross-over design is the carry over effects between treatments which can be avoided by a long wash-out period between treatments and by selecting the duration of each treatment based on the knowledge of the disease and medication. In comparison Parallel group design is simple and does not have any residual or carry over effects but is usually done to confirm therapeutic dose of a new drug at different doses, against a placebo or standard treatment. The limitations of crossover design is that it is difficult to use in conditions which fluctuate over a short term basis such as acute migraine but it is best suited for chronic stable diseases such as chronic migraine.

For Professor Smith to decide if his new treatment is better than the standard treatment, he has to consider the results from the double blind crossover clinical trials of his new drug against aspirin. The result could be a positive result which means his new drug is better and more effective than the standard treatment, or negative showing that the new drug is less effective than the standard treatment. Other outcomes of the clinical trials is that they can be inconclusive showing that the new drug is neither more effective or less than standard treatment, or non-inferior were the clinical trial result shows the new drug is equivalent to standard treatment.

Patient compliance during clinical trial is an issue because only one third of patients comply with their treatment, while another one-third partly comply and the rest never comply [13] . This is usually due to different reasons such as

On phase I drug testing: "The requirement…of Article III.2, 'subjects should be volunteers - either healthy persons or patients for whom the experimental design is not related to the patient's illness' is not to be disregarded lightly."